tbuckley/cabot-search huggingface dataset:
Indolent cancer and pattern of progression: Two missing parameters in trial design for hepatology
Authors: Massimo Iavarone, Jean-Charles Nault, Giuseppe Cabibbo, Ferran Torres, Maria Reig
Journal: Hepatology (2023)

The indolent and aggressive behaviors of HCC might have a role in clinical trial (CT) results; however, the indolent HCC is less analyzed compared to others cancer. Indolent profile could be characterized as follows: (1) patients with low risk of progression itself due to the HCC molecular profile and/or due to the interaction between cancer cell their microenvironment; (2) patients who achieve objective response or present spontaneous regression; and (3) patients who develop radiological progression with no consequence on either the liver function or general status, and without trigger a change in the tumor stage. Patients with “indolent HCC” generally never develop cancer-related symptoms neither die for HCC-related causes. Thus, we hypothesize that the imbalance in the proportion of “indolent” versus “aggressive HCC” between arms or the underestimation/overestimation of HCC behavior at baseline in single-arm CT could be associated with CT failure or under-overestimation of trial results. The “indolent progression” may also explain the discrepancy between radiological progression-based end points and survival. Moreover, we discuss the related causes that explain the indolent profile of HCC and propose (1) refining the progression-related end point by the pattern of progression to minimize the limitations of the current end points; (2) considering alternative statistical tools for survival analysis such as milestone survival, or restricted mean survival time to capture the value of indolent HCC. According to these considerations, we propose incorporating novel end points into the single arm of phase I/II CT as exploratory analysis or as a secondary end point in phase III CT.
<i>In vitro</i> adhesion, pilus expression, and <i>in vivo</i> amelioration of antibiotic-induced microbiota disturbance by <i>Bifidobacterium</i> spp. strains from fecal donors
Authors: Aki Ronkainen, Imran Khan, Eva Krzyżewska-Dudek, Kaisa Hiippala, Tobias L. Freitag, Reetta Satokari
Journal: Gut Microbes (2023)

Fecal microbiota transplantation (FMT) is used routinely to treat recurrent Clostridioides difficile infection (rCDI) and investigated as a treatment for numerous conditions associated with gut microbiota alterations. Metagenomic analyses have indicated that recipient colonization by donor bacteria may be associated with favorable clinical outcomes. Bifidobacteria are abundant gut commensals associated with health. We have previously demonstrated that Bifidobacterium strains transferred in FMT can colonize recipients in long term, at least for a year, and recovered such strains by cultivation. This study addressed in vitro adhesion and pilus gene expression of long-term colonizing Bifidobacterium strains from FMT donors as well as in vivo colonization and capability to ameliorate antibiotic-induced microbiota disturbance. RNA-Seq differential gene expression analysis showed that the strongly adherent B. longum strains DY_pv11 and DX_pv23 expressed tight adherence and sortase-dependent pilus genes, respectively. Two B. longum strains, adherent DX_pv23 and poorly adhering DX_pv18, were selected to address in vivo colonization and efficacy to restore antibiotic-disturbed microbiota in C57BL/6 murine model. DX_pv23 colonized mice transiently with a rate comparable to that of the B. animalis BB-12 used as a reference. Although long-term colonization was not observed with any of the three strains, 16S rRNA gene profiling revealed that oral administration of DX_pv23 enhanced the recovery of antibiotic-disturbed microbiota to the original configuration significantly better than the other strains. The findings suggest that selected strains from FMT donors, such as DX_pv23 in this study, may have therapeutic potential by in vitro expression of colonization factors and boosting endogenous gut microbiota.
Survival From Birth Until Young Adulthood Among Individuals With Congenital Heart Defects: CH STRONG
Authors: Karrie F. Downing, Wendy N. Nembhard, Charles E. Rose, Jennifer G. Andrews, Anthony Goudie, Scott E. Klewer, Matthew E. Oster, Sherry L. Farr
Journal: Circulation (2023)

Limited population-based information is available on long-term survival of US individuals with congenital heart defects (CHDs). Therefore, we assessed patterns in survival from birth until young adulthood (ie, 35 years of age) and associated factors among a population-based sample of US individuals with CHDs.
Hepatocellular carcinoma surveillance may be associated with potential psychological harms in patients with cirrhosis
Authors: Manasa Narasimman, Ruben Hernaez, Vanessa Cerda, MinJae Lee, Anubha Sood, Sruthi Yekkaluri, Aisha Khan, Lisa Quirk, Yan Liu, Jennifer R. Kramer, Simon Craddock Lee, Caitlin C. Murphy, Jasmin A. Tiro, Amit G. Singal
Journal: Hepatology (2023)

Background and Aims: The value of HCC surveillance is determined by the balance between benefits and harms; however, no studies have enumerated psychological harms. Approach and Results: We fielded surveys measuring psychological harms to patients with cirrhosis in a multicenter randomized trial of HCC surveillance outreach. All patients with positive or indeterminate surveillance results and matched patients with negative results were invited to complete surveys measuring (1) depression through the Patient Health Questionnaire-ninth version, (2) anxiety through State-Trait Anxiety Inventory, (3) HCC-specific worry through Psychological Consequences Questionnaire, and (4) decisional regret. Patients were classified into 4 groups: true positive (TP), false positive (FP), indeterminate, and true negative (TN). Multivariable longitudinal regression analysis using the generalized estimating equation method was performed to compare the means of measures across groups. We conducted 89 semistructured interviews in a subset of patients stratified by health system and test results. Of 2872 patients in the trial, 311 completed 1+ follow-up survey (63 FP, 77 indeterminate, 38 TP, and 133 TN). Moderate depression decreased in TN patients, increased in TP, and had intermittent but mild increases in those with FP and indeterminate results. High anxiety temporarily increased in patients with TP results but resolved over time and was stable in those with FP and indeterminate results. Decisional regret was low and did not differ across groups. In semistructured interviews, patients reported apprehension, anxiety, emotional distress, and coping related to HCC surveillance. Conclusions: Psychological harms of HCC surveillance appear mild but differ by test result. Future research should determine the impact of psychological harms on the value of HCC surveillance programs.
Diet high in linoleic acid dysregulates the intestinal endocannabinoid system and increases susceptibility to colitis in Mice
Authors: Poonamjot Deol, Paul Ruegger, Geoffrey D. Logan, Ali Shawki, Jiang Li, Jonathan D. Mitchell, Jacqueline Yu, Varadh Piamthai, Sarah H. Radi, Sana Hasnain, Kamil Borkowski, John W. Newman, Declan F. McCole, Meera G. Nair, Ansel Hsiao, James Borneman, Frances M. Sladek
Journal: Gut Microbes (2023)

Inflammatory bowel disease (IBD) is a multifactorial disease with increasing incidence in the U.S. suggesting that environmental factors, including diet, are involved. It has been suggested that excessive consumption of linoleic acid (LA, C18:2 omega-6), which must be obtained from the diet, may promote the development of IBD in humans. To demonstrate a causal link between LA and IBD, we show that a high fat diet (HFD) based on soybean oil (SO), which is comprised of ~55% LA, increases susceptibility to colitis in several models, including IBD-susceptible IL10 knockout mice. This effect was not observed with low-LA HFDs derived from genetically modified soybean oil or olive oil. The conventional SO HFD causes classical IBD symptoms including immune dysfunction, increased intestinal epithelial barrier permeability, and disruption of the balance of isoforms from the IBD susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α). The SO HFD causes gut dysbiosis, including increased abundance of an endogenous adherent invasive Escherichia coli (AIEC), which can use LA as a carbon source. Metabolomic analysis shows that in the mouse gut, even in the absence of bacteria, the presence of soybean oil increases levels of LA, oxylipins and prostaglandins. Many compounds in the endocannabinoid system, which are protective against IBD, are decreased by SO both in vivo and in vitro. These results indicate that a high LA diet increases susceptibility to colitis via microbial and host-initiated pathways involving alterations in the balance of bioactive metabolites of omega-6 and omega-3 polyunsaturated fatty acids, as well as HNF4α isoforms.
<i>Limosilactobacillus reuteri</i> DSM 17938 supplementation and SARS-CoV-2 specific antibody response in healthy adults: a randomized, triple-blinded, placebo-controlled trial
Authors: Richard A. Forsgård, Julia Rode, Karin Lobenius-Palmér, Annalena Kamm, Snehal Patil, Mirriam G. J. Tacken, Marleen A. H. Lentjes, Jakob Axelsson, Gianfranco Grompone, Scott Montgomery, Robert J. Brummer
Journal: Gut Microbes (2023)

Studies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 μg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 μg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168-1480] BAU/ml vs 111 [36.1-1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212-3449] BAU/ml vs (83.7 [22.8-2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9-976] BAU/ml vs 61.3 [26.7-97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.
Impact of comorbidities on health status measured using the Kansas City Cardiomyopathy Questionnaire in patients with heart failure with reduced and preserved ejection fraction
Authors: Mingming Yang, Toru Kondo, Carly Adamson, Jawad H. Butt, William T. Abraham, Akshay S. Desai, Karola S. Jering, Lars Køber, Mikhail N. Kosiborod, Milton Packer, Jean L. Rouleau, Scott D. Solomon, Muthiah Vaduganathan, Michael R. Zile, Pardeep S. Jhund, John J.V. McMurray
Journal: European Journal of Heart Failure (2023)

Patients with heart failure (HF) often suffer from a range of comorbidities, which may affect their health status. The aim of this study was to assess the impact of different comorbidities on health status in patients with HF and reduced (HFrEF) and preserved ejection fraction (HFpEF).Using individual patient data from HFrEF (ATMOSPHERE, PARADIGM-HF, DAPA-HF) and HFpEF (TOPCAT, PARAGON-HF) trials, we examined the Kansas City Cardiomyopathy Questionnaire (KCCQ) domain scores and overall summary score (KCCQ-OSS) across a range of cardiorespiratory (angina, atrial fibrillation [AF], stroke, chronic obstructive pulmonary disease [COPD]) and other comorbidities (obesity, diabetes, chronic kidney disease [CKD], anaemia). Of patients with HFrEF (n = 20 159), 36.2% had AF, 33.9% CKD, 33.9% diabetes, 31.4% obesity, 25.5% angina, 12.2% COPD, 8.4% stroke, and 4.4% anaemia; the corresponding proportions in HFpEF (n = 6563) were: 54.0% AF, 48.7% CKD, 43.4% diabetes, 53.3% obesity, 28.6% angina, 14.7% COPD, 10.2% stroke, and 6.5% anaemia. HFpEF patients had lower KCCQ domain scores and KCCQ-OSS (67.8 vs. 71.3) than HFrEF patients. Physical limitations, social limitations and quality of life domains were reduced more than symptom frequency and symptom burden domains. In both HFrEF and HFpEF, COPD, angina, anaemia, and obesity were associated with the lowest scores. An increasing number of comorbidities was associated with decreasing scores (e.g. KCCQ-OSS 0 vs. ≥4 comorbidities: HFrEF 76.8 vs. 66.4; HFpEF 73.7 vs. 65.2).Cardiac and non-cardiac comorbidities are common in both HFrEF and HFpEF patients and most are associated with reductions in health status although the impact varied among comorbidities, by the number of comorbidities, and by HF phenotype. Treating/correcting comorbidity is a therapeutic approach that may improve the health status of patients with HF.
Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens
Authors: Forough Chelangarimiyandoab, Priyanka Mungara, Manav Batta, Emmanuelle Cordat
Journal: Journal of the American Society of Nephrology (2023)

Urinary tract infections affect more than 1 in 2 women during their lifetime. Among these, more than 10% of patients carry antibiotic-resistant bacterial strains, highlighting the urgent need to identify alternative treatments. While innate defense mechanisms are well-characterized in the lower urinary tract, it is becoming evident that the collecting duct (CD), the first renal segment encountered by invading uropathogenic bacteria, also contributes to bacterial clearance. However, the role of this segment is beginning to be understood. This review summarizes the current knowledge on CD intercalated cells in urinary tract bacterial clearance. Understanding the innate protective role of the uroepithelium and of the CD offers new opportunities for alternative therapeutic strategies.
Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery
Authors: Kamrouz Ghadimi, Jhaymie L. Cappiello, Mary Cooter Wright, Jerrold H. Levy, Benjamin S. Bryner, Adam D. DeVore, Jacob N. Schroder, Chetan B. Patel, Sudarshan Rajagopal, Svati H. Shah, Carmelo A. Milano
Journal: Circulation (2023)

Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy.
Stretch Harmonizes Sarcomere Strain Across the Cardiomyocyte
Authors: Jia Li, Joakim Sundnes, Yufeng Hou, Martin Laasmaa, Marianne Ruud, Andreas Unger, Terje R. Kolstad, Michael Frisk, Per Andreas Norseng, Limin Yang, Ingunn E. Setterberg, Estela S. Alves, Michaeljohn Kalakoutis, Ole M. Sejersted, Johanna T. Lanner, Wolfgang A. Linke, Ida G. Lunde, Pieter P. de Tombe, William E. Louch
Journal: Circulation Research (2023)

Increasing cardiomyocyte contraction during myocardial stretch serves as the basis for the Frank-Starling mechanism in the heart. However, it remains unclear how this phenomenon occurs regionally within cardiomyocytes, at the level of individual sarcomeres. We investigated sarcomere contractile synchrony and how intersarcomere dynamics contribute to increasing contractility during cell lengthening.
Better together– <i>Salmonella</i> biofilm-associated antibiotic resistance
Authors: Adrianna Aleksandrowicz, Ewa Carolak, Agata Dutkiewicz, Aleksandra Błachut, Wiktoria Waszczuk, Krzysztof Grzymajlo
Journal: Gut Microbes (2023)

Salmonella poses a serious threat to public health and socioeconomic development worldwide because of its foodborne pathogenicity and antimicrobial resistance. This biofilm-planktonic lifestyle enables Salmonella to interfere with the host and become resistant to drugs, conferring inherent tolerance to antibiotics. The complex biofilm structure makes bacteria tolerant to harsh conditions due to the diversity of physiological, biochemical, environmental, and molecular factors constituting resistance mechanisms. Here, we provide an overview of the mechanisms of Salmonella biofilm formation and antibiotic resistance, with an emphasis on less-studied molecular factors and in-depth analysis of the latest knowledge about upregulated drug-resistance-associated genes in bacterial aggregates. We classified and extensively discussed each group of these genes encoding transporters, outer membrane proteins, enzymes, multiple resistance, metabolism, and stress response-associated proteins. Finally, we highlighted the missing information and studies that need to be undertaken to understand biofilm features and contribute to eliminating antibiotic-resistant and health-threatening biofilms.
Reply to Jang et al. ‘s commentary on Yue et al.: Efficacy and tolerability of pharmacological treatments for insomnia in adults: A systematic review and network meta-analysis
Authors: Jing-Li Yue, Xiang-Wen Chang, Jun-Wei Zheng, Le Shi, Ya-Jie Xiang, Jian-Yu Que, Kai Yuan, Jia-Hui Deng, Teng Teng, Yang-Yang Li, Wei Sun, Hong-Qiang Sun, Michael V. Vitiello, Xiang-Dong Tang, Xin-Yu Zhou, Yan-Ping Bao, Jie Shi, Lin Lu
Journal: Sleep Medicine Reviews (2023)
Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling
Authors: Long Long Cao, Heng Lu, Mohammed Soutto, Nadeem Bhat, Zheng Chen, Dunfa Peng, Ahmed Gomaa, Jia Bin Wang, Jian Wei Xie, Ping Li, Chao Hui Zheng, Sachiyo Nomura, Jashodeep Datta, Nipun Merchant, Zhi Bin Chen, Alejandro Villarino, Alexander Zaika, Chang Ming Huang, Wael El-Rifai
Journal: Gut (2023)

Objective Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. Design A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. Results Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like ‘cold’ tumours to CTLA4 blockade. Conclusion Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ ‘cold’ GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.
Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with Alzheimer's disease and diabetes
Authors: Yue Tian, Guangchan Jing, Mengren Zhang
Journal: Ageing Research Reviews (2023)

Accumulation of amyloid-β in the central nervous system is a common feature of Alzheimer's disease (AD) and diabetes-related cognitive impairment. Since the insulin-degrading enzyme (IDE) can break down amyloid-β plaques, there is considerable interest in using this enzyme to treat both neurological disorders. In this review, we have summarized the pre-clinical and clinical research on the potential application of IDE for the improvement of cognitive impairment. Furthermore, we have presented an overview of the main pathways that can be targeted to mitigate the progression of AD and the cognitive impairment caused by diabetes.
Building a better understanding of adult social care
Authors: Jon Glasby, Clenton Farquharson, Liz Hanson, Mirella Minkman
Journal: BMJ (2023)

This was particularly apparent dur- ing the pandemic, with tragic consequences• We need to raise awareness of the importance of social care (with policy makers and the broader public), better understand the breadth of the contribution it makes, and develop a more positive vision for adult social care more generally on 18 August
Characterization of large-scale genomic differences in the first complete human genome
Authors: Xiangyu Yang, Xuankai Wang, Yawen Zou, Shilong Zhang, Manying Xia, Lianting Fu, Mitchell R. Vollger, Nae-Chyun Chen, Dylan J. Taylor, William T. Harvey, Glennis A. Logsdon, Dan Meng, Junfeng Shi, Rajiv C. McCoy, Michael C. Schatz, Weidong Li, Evan E. Eichler, Qing Lu, Yafei Mao
Journal: Genome biology (2023)

The first telomere-to-telomere (T2T) human genome assembly (T2T-CHM13) release is a milestone in human genomics. The T2T-CHM13 genome assembly extends our understanding of telomeres, centromeres, segmental duplication, and other complex regions. The current human genome reference (GRCh38) has been widely used in various human genomic studies. However, the large-scale genomic differences between these two important genome assemblies are not characterized in detail yet.Here, in addition to the previously reported "non-syntenic" regions, we find 67 additional large-scale discrepant regions and precisely categorize them into four structural types with a newly developed website tool called SynPlotter. The discrepant regions (~ 21.6 Mbp) excluding telomeric and centromeric regions are highly structurally polymorphic in humans, where the deletions or duplications are likely associated with various human diseases, such as immune and neurodevelopmental disorders. The analyses of a newly identified discrepant region-the KLRC gene cluster-show that the depletion of KLRC2 by a single-deletion event is associated with natural killer cell differentiation in ~ 20% of humans. Meanwhile, the rapid amino acid replacements observed within KLRC3 are probably a result of natural selection in primate evolution.Our study provides a foundation for understanding the large-scale structural genomic differences between the two crucial human reference genomes, and is thereby important for future human genomics studies.